17-64055698-G-C

Position:

• chr17-64055698-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000433197.4(ERN1):​c.1649C>G​(p.Pro550Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,600,718 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (8 hom.)
• Consequence: ERN1 ENST00000433197.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.93

Genes affected

ERN1 (HGNC:3449): (endoplasmic reticulum to nucleus signaling 1) This gene encodes the transmembrane protein kinase inositol-requiring enzyme 1. The encoded protein contains two functional catalytic domains, a serine/threonine-protein kinase domain and an endoribonuclease domain. This protein functions as a sensor of unfolded proteins in the endoplasmic reticulum (ER) and triggers an intracellular signaling pathway termed the unfolded protein response (UPR). The UPR is an ER stress response that is conserved from yeast to mammals and activates genes involved in degrading misfolded proteins, regulating protein synthesis and activating molecular chaperones. This protein specifically mediates the splicing and activation of the stress response transcription factor X-box binding protein 1. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045041144).
• BP6: Variant 17-64055698-G-C is Benign according to our data. Variant chr17-64055698-G-C is described in ClinVar as [Benign]. Clinvar id is 711689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0064 (975/152350) while in subpopulation AFR AF= 0.0226 (939/41576). AF 95% confidence interval is 0.0214. There are 8 homozygotes in gnomad4. There are 444 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 975 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERN1	NM_001433.5	c.1649C>G	p.Pro550Arg	missense_variant	13/22	ENST00000433197.4	NP_001424.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERN1	ENST00000433197.4	c.1649C>G	p.Pro550Arg	missense_variant	13/22	1	NM_001433.5	ENSP00000401445	P1
ERN1	ENST00000680433.1	c.1649C>G	p.Pro550Arg	missense_variant	13/20			ENSP00000506094
ERN1	ENST00000680625.1	n.1567C>G		non_coding_transcript_exon_variant	12/21

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 975 AN: 152232 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00160 AC: 378 AN: 236730 Hom.: 4 AF XY: 0.00116 AC XY: 150 AN XY: 128904

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.000681

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000655

Gnomad OTH exome AF: 0.000352

GnomAD4 exome AF: 0.000678 AC: 982 AN: 1448368 Hom.: 8 Cov.: 32 AF XY: 0.000567 AC XY: 408 AN XY: 719284

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000826

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000253

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00640 AC: 975 AN: 152350 Hom.: 8 Cov.: 32 AF XY: 0.00596 AC XY: 444 AN XY: 74512

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00176 Hom.: 1

Bravo AF: 0.00734

ESP6500AA AF: 0.0169 AC: 70

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00180 AC: 218

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.29	T
Polyphen		0.70	P
Vest4		0.19
MVP		0.59
MPC		0.48
ClinPred		0.015	T
GERP RS		-0.30
Varity_R		0.058
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61736503; hg19: chr17-62133058; COSMIC: COSV99068259; COSMIC: COSV99068259;